Stromal fibroblasts facilitate cancer cell invasion by a novel invadopodia-independent matrix degradation process

H. Cao, R. D. Eppinga, Gina Razidlo, E. W. Krueger, J. Chen, L. Qiang, Mark A Mc Niven

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Metastatic invasion of tumors into peripheral tissues is known to rely upon protease-mediated degradation of the surrounding stroma. This remodeling process uses complex, actin-based, specializations of the plasma membrane termed invadopodia that act both to sequester and release matrix metalloproteinases. Here we report that cells of mesenchymal origin, including tumor-associated fibroblasts, degrade substantial amounts of surrounding matrix by a mechanism independent of conventional invadopodia. These degradative sites lack the punctate shape of conventional invadopodia to spread along the cell base and are reticular and/or fibrous in character. In marked contrast to invadopodia, this degradation does not require the action of Src kinase, Cdc42 or Dyn2. Rather, inhibition of Dyn2 causes a marked upregulation of stromal matrix degradation. Further, expression and activity of matrix metalloproteinases are differentially regulated between tumor cells and stromal fibroblasts. This matrix remodeling by fibroblasts increases the invasive capacity of tumor cells, thereby illustrating how the tumor microenvironment can contribute to metastasis. These findings provide evidence for a novel matrix remodeling process conducted by stromal fibroblasts that is substantially more effective than conventional invadopodia, distinct in structural organization and regulated by disparate molecular mechanisms.

Original languageEnglish (US)
Pages (from-to)1099-1110
Number of pages12
JournalOncogene
Volume35
Issue number9
DOIs
StatePublished - Mar 3 2016

Fingerprint

Fibroblasts
Neoplasms
Matrix Metalloproteinases
Tumor Microenvironment
src-Family Kinases
Stromal Cells
Actins
Peptide Hydrolases
Up-Regulation
Cell Membrane
Podosomes
Neoplasm Metastasis

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Stromal fibroblasts facilitate cancer cell invasion by a novel invadopodia-independent matrix degradation process. / Cao, H.; Eppinga, R. D.; Razidlo, Gina; Krueger, E. W.; Chen, J.; Qiang, L.; Mc Niven, Mark A.

In: Oncogene, Vol. 35, No. 9, 03.03.2016, p. 1099-1110.

Research output: Contribution to journalArticle

Cao, H. ; Eppinga, R. D. ; Razidlo, Gina ; Krueger, E. W. ; Chen, J. ; Qiang, L. ; Mc Niven, Mark A. / Stromal fibroblasts facilitate cancer cell invasion by a novel invadopodia-independent matrix degradation process. In: Oncogene. 2016 ; Vol. 35, No. 9. pp. 1099-1110.
@article{8c6da865298f476e8fdbe010ba32d7b8,
title = "Stromal fibroblasts facilitate cancer cell invasion by a novel invadopodia-independent matrix degradation process",
abstract = "Metastatic invasion of tumors into peripheral tissues is known to rely upon protease-mediated degradation of the surrounding stroma. This remodeling process uses complex, actin-based, specializations of the plasma membrane termed invadopodia that act both to sequester and release matrix metalloproteinases. Here we report that cells of mesenchymal origin, including tumor-associated fibroblasts, degrade substantial amounts of surrounding matrix by a mechanism independent of conventional invadopodia. These degradative sites lack the punctate shape of conventional invadopodia to spread along the cell base and are reticular and/or fibrous in character. In marked contrast to invadopodia, this degradation does not require the action of Src kinase, Cdc42 or Dyn2. Rather, inhibition of Dyn2 causes a marked upregulation of stromal matrix degradation. Further, expression and activity of matrix metalloproteinases are differentially regulated between tumor cells and stromal fibroblasts. This matrix remodeling by fibroblasts increases the invasive capacity of tumor cells, thereby illustrating how the tumor microenvironment can contribute to metastasis. These findings provide evidence for a novel matrix remodeling process conducted by stromal fibroblasts that is substantially more effective than conventional invadopodia, distinct in structural organization and regulated by disparate molecular mechanisms.",
author = "H. Cao and Eppinga, {R. D.} and Gina Razidlo and Krueger, {E. W.} and J. Chen and L. Qiang and {Mc Niven}, {Mark A}",
year = "2016",
month = "3",
day = "3",
doi = "10.1038/onc.2015.163",
language = "English (US)",
volume = "35",
pages = "1099--1110",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "9",

}

TY - JOUR

T1 - Stromal fibroblasts facilitate cancer cell invasion by a novel invadopodia-independent matrix degradation process

AU - Cao, H.

AU - Eppinga, R. D.

AU - Razidlo, Gina

AU - Krueger, E. W.

AU - Chen, J.

AU - Qiang, L.

AU - Mc Niven, Mark A

PY - 2016/3/3

Y1 - 2016/3/3

N2 - Metastatic invasion of tumors into peripheral tissues is known to rely upon protease-mediated degradation of the surrounding stroma. This remodeling process uses complex, actin-based, specializations of the plasma membrane termed invadopodia that act both to sequester and release matrix metalloproteinases. Here we report that cells of mesenchymal origin, including tumor-associated fibroblasts, degrade substantial amounts of surrounding matrix by a mechanism independent of conventional invadopodia. These degradative sites lack the punctate shape of conventional invadopodia to spread along the cell base and are reticular and/or fibrous in character. In marked contrast to invadopodia, this degradation does not require the action of Src kinase, Cdc42 or Dyn2. Rather, inhibition of Dyn2 causes a marked upregulation of stromal matrix degradation. Further, expression and activity of matrix metalloproteinases are differentially regulated between tumor cells and stromal fibroblasts. This matrix remodeling by fibroblasts increases the invasive capacity of tumor cells, thereby illustrating how the tumor microenvironment can contribute to metastasis. These findings provide evidence for a novel matrix remodeling process conducted by stromal fibroblasts that is substantially more effective than conventional invadopodia, distinct in structural organization and regulated by disparate molecular mechanisms.

AB - Metastatic invasion of tumors into peripheral tissues is known to rely upon protease-mediated degradation of the surrounding stroma. This remodeling process uses complex, actin-based, specializations of the plasma membrane termed invadopodia that act both to sequester and release matrix metalloproteinases. Here we report that cells of mesenchymal origin, including tumor-associated fibroblasts, degrade substantial amounts of surrounding matrix by a mechanism independent of conventional invadopodia. These degradative sites lack the punctate shape of conventional invadopodia to spread along the cell base and are reticular and/or fibrous in character. In marked contrast to invadopodia, this degradation does not require the action of Src kinase, Cdc42 or Dyn2. Rather, inhibition of Dyn2 causes a marked upregulation of stromal matrix degradation. Further, expression and activity of matrix metalloproteinases are differentially regulated between tumor cells and stromal fibroblasts. This matrix remodeling by fibroblasts increases the invasive capacity of tumor cells, thereby illustrating how the tumor microenvironment can contribute to metastasis. These findings provide evidence for a novel matrix remodeling process conducted by stromal fibroblasts that is substantially more effective than conventional invadopodia, distinct in structural organization and regulated by disparate molecular mechanisms.

UR - http://www.scopus.com/inward/record.url?scp=84959544725&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84959544725&partnerID=8YFLogxK

U2 - 10.1038/onc.2015.163

DO - 10.1038/onc.2015.163

M3 - Article

C2 - 25982272

AN - SCOPUS:84959544725

VL - 35

SP - 1099

EP - 1110

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 9

ER -